Abstract
Effector-T-cell-mediated immunity depends on the efficient localization of antigen-primed lymphocytes to antigen-rich non-lymphoid tissue, which is facilitated by the expression of a unique set of "homing" receptors acquired by memory T cells. We report that engagement of the hepatocyte growth factor (HGF) receptor c-Met by heart-produced HGF during priming in the lymph nodes instructs T cell cardiotropism, which was associated with a specialized homing "signature" (c-Met(+)CCR4(+)CXCR3(+)). c-Met signals facilitated T cell recruitment to the heart via the chemokine receptor CCR5 by inducing autocrine CCR5 ligand release. c-Met triggering was sufficient to support cardiotropic T cell recirculation, while CCR4 and CXCR3 sustained recruitment during heart inflammation. Transient pharmacological blockade of c-Met during T cell priming led to enhanced survival of heart, but not skin, allografts associated with impaired localization of alloreactive T cells to heart grafts. These findings suggest c-Met as a target for development of organ-selective immunosuppressive therapies.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Autocrine Communication
-
Cell Movement / drug effects
-
Cell Movement / genetics
-
Cells, Cultured
-
Graft Rejection / etiology
-
Graft Rejection / genetics
-
Graft Rejection / prevention & control*
-
Heart / physiology*
-
Heart Transplantation*
-
Hepatocyte Growth Factor / metabolism*
-
Humans
-
Immunologic Memory
-
Indoles / pharmacology
-
Lymphocyte Activation / drug effects
-
Lymphocyte Activation / genetics
-
Mice
-
Mice, SCID
-
Molecular Targeted Therapy
-
Proto-Oncogene Proteins c-met / antagonists & inhibitors
-
Proto-Oncogene Proteins c-met / genetics
-
Proto-Oncogene Proteins c-met / metabolism*
-
RNA, Small Interfering / genetics
-
Receptors, CCR5 / metabolism
-
Receptors, Chemokine / metabolism
-
Receptors, Lymphocyte Homing / metabolism
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
Sulfones / pharmacology
-
T-Lymphocytes / drug effects
-
T-Lymphocytes / physiology*
Substances
-
5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
-
CCR5 protein, mouse
-
Indoles
-
RNA, Small Interfering
-
Receptors, CCR5
-
Receptors, Chemokine
-
Receptors, Lymphocyte Homing
-
Sulfones
-
Hepatocyte Growth Factor
-
Proto-Oncogene Proteins c-met